Process for preparing tannate liquid and semi-solid dosage forms

ABSTRACT

An active ingredient from the group of an antihistamine, a decongestant, an antitussive or anticholinergic is dissolved in a suitable solvent and added to a dispersion of tannic acid in water to form the tannate salt complex of the active ingredient. The active ingredient tannate salt complex without isolation or purification is then added to a liquid or semi-solid medium composed of thickening, suspending, coloring, sweetening and flavoring agents, with stirring. Thereafter, preservatives, pH-adjusting and anti-caking agents in a suitable solvent are mixed with the liquid or semi-solid medium to generate a therapeutic dosage form.

[0001] This application is a continuation-in-part from provisionalapplication Serial No. 60/282,969, filed Apr. 10, 2001.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates generally to the field of tannatechemistry and more specifically to methods for processing tannatesuspensions.

[0004] 2. Description of the Prior Art

[0005] The use of tannate suspensions for pharmaceutical use iswell-known. U.S. Pat. No. 6,287,597 describes tannate suspensionscontaining pyrilamine tannate and phenylephrine tannate. The suspensionis prepared in a conventional manner such that one teaspoon contains 30mg pyrilamine tannate and 5 mg phenylephrine tannate with benzoic acid,coloring agent, natural and artificial flavors, glycerin, kaolin,magnesium aluminum silicate, methyl paraben, pectin, purified water,saccharin, sodium hydroxide and sucrose or sorbitol. The January 1990issue of Annals of Allergy, Volume 64, describes combinations ofchlorpheniramine tannate, pyrilamine tannate and phenylephrine tannate.An article in Clinical Medicine, dated September 1965, pages 1475-1478describes tablets of pyrilamine tannate, chlorpheniramine tannate andamphetamine tannate. Phenylephrine tannate compositions are disclosed inU.S. Pat. No. 5,599,846 and phenylephrine tannate and chlorpheniraminetannate compositions are disclosed in U.S. Pat. No. 6,037,358. None ofthese references suggest or describe the production of a suspension bymeans of an in-situ conversion to the tannate salt of the activeingredient to provide a dosage form which affords a sustained release ofthe active ingredient over prolonged intervals of time. Such asuspension is needed to improve patient compliance with dosagerequirements.

SUMMARY OF THE INVENTION

[0006] The present invention provides a manufacturing process forin-situ conversion and incorporation thereof, of tannate salt complexesof antihistamine, antitussive, decongestant and anticholinergic class ofpharmaceutical compounds into a sustained release therapeutic liquid orsemi-solid dosage form. By starting with a commonly available salt orfree base of the active pharmaceutical ingredient, which is subsequentlyconverted and incorporated in-situ as a tannate salt complex, theinvention provides an efficient and reproducible method to manufactureliquid or semi-solid products containing tannate salt complexes asactive ingredients.

[0007] The process provides the addition of the active ingredient to adispersion of tannic acid to generate a tannate salt complex. Thepresence of the dispersing agent prevents the clumping and aggregationof the tannate salt complex formed. Without further treatment,excipients such as thickening, suspending, coloring, sweetening andflavoring agents are therefore added to water under stirring, to form adispersion. Preservatives, pH adjusting and anti-caking agents are addedto suitable solvent under stirring to form a dispersion. After combiningthe dispersions a suspension dosage form, at a pH of 3.5-8.0 is thefinal result.

[0008] By forming a suspension of the tannate salt complex of theactive, the process provides a dosage form, which affords a sustainedrelease of the active pharmaceutical ingredients over prolongedintervals of time, thereby improving patient compliance factors.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention involves a novel manufacturing process forthe preparation of liquid or semi-solid dosage forms containing atannate salt complex of active pharmaceutical ingredients (API). Thisincludes a conversion process which includes the steps of mixing adispersing agent and tannic acid in a suitable solvent to generate amixture in liquid form. The API as a salt or in the free base form iscombined with the dispersing agent/tannic acid mixture to generate thetannate salt complex. The presence of the dispersing agent prevents theclumping and aggregation of the tannate salt complex formed and promotesuniformity in the solution. The conversion process requires the presenceof basic functional groups such as amines and sulfoxides in themolecular structure of the API. The formation of the tannate salt is byreaction of amine groups (in the 1°, 2°, 3°, 4°, or amphotericfunctional states) or of the other basic functional groups with tannicacid. The amount and ratio of dispersing agent and tannic acid, requiredfor the completion of the reaction, is determined by the molecularconfiguration and concentration of the API.

[0010] Tannate salt complexes of active ingredients have been found tohave better organoleptic properties such as taste, in comparison toother salts or free base forms. In addition, the tannate salt complex ofthe active is a significantly larger molecule, which affords absorptionof the active over prolonged intervals of time, reducing the frequencyof administration and thereby improves patient compliance factors.

[0011] Because of the large tannate molecule, the percentage ofantihistamine or decongestant free base within the tannate salt issignificantly lower than that in other salt forms such as thehydrochloride or maleate. The presence of low active percentages and thevariable purity of the commercially available tannate salts leads to thestoichiometry of the active free base to tannic acid in the tannatesalts to be different from batch to batch. This could cause significantdosing and processing problems during manufacture and increase thelikelihood that commercially available pharmaceutical products containvariable and in some instances sub-therapeutic levels of said activedrug substances. Therefore, it would be desirable if pharmaceuticalcompositions containing tannate salts of active ingredients could beprepared with reduced variability in active drug content and increasedcertainty that the actives are delivered within the therapeutic range.

[0012] By starting with a known amount of commonly available salt or thefree base form of the API, which is subsequently converted andincorporated in-situ as a tannate salt, the invention provides anefficient and reproducible method to manufacture products containingtannate salts as active ingredients. Since the tannate salt of the APIis generated and incorporated in-situ into the dosage form during themanufacturing process, the purification and drying steps required forthe isolation of the tannate salt are eliminated and the stoichiometryof the tannate salt is uniform from batch to batch.

[0013] The active pharmaceutical ingredients (API) are selected from thegroup as follows:

[0014] Antihistamines:

[0015] (1) Carbinoxamine

[0016] (2) Chlorpheniramine

[0017] (3) Pyrilamine

[0018] (4) Pheniramine

[0019] (5) Phenindamine

[0020] (6) Diphenhydramine

[0021] (7) Bromodiphenhydramine

[0022] (8) Bromphenirmaine

[0023] (9) Loratadine

[0024] (10) Desloratadine

[0025] (11) Fexofenadine

[0026] (12) Cetirizine

[0027] (13) Hydroxyzine

[0028] (14) Promethazine

[0029] (15) Acrivastine

[0030] (16) Triprolidine

[0031] (17) Meclizine

[0032] (18) Dimenhydrinate

[0033] (19) Triplennamine

[0034] (20) Doxylamine

[0035] (21) Diphenylpyrilamine

[0036] (22) Trimeprazine

[0037] (23) Chlorcylizine

[0038] Antitussives:

[0039] (1) Carbetapentane

[0040] (2) Dextromethorphan

[0041] (3) Diphenhydramine

[0042] (4) Codeine

[0043] (5) Hydrocodone

[0044] (6) Oxycodone

[0045] (7) Morphine

[0046] Decongestants:

[0047] (1) Phenylephrine

[0048] (2) Pseudoephedrine

[0049] (3) Ephedrine

[0050] (4) Diphenhydramine

[0051] (5) Cyproheptadine

[0052] (6) Phenyltoloxamine

[0053] (7) Clemastine

[0054] Anticholinergics:

[0055] (1) Methscopolamine.

[0056] The active pharmacologic ingredients are used as the free basesor as salts having anionic functional groups such as bitartrate,maleate, citrate, chloride, bromide, acetate and sulfate. The source ofthe tannic acid is natural or synthetic.

[0057] The preferred dispersing agent is chosen from the group such asmagnesium aluminum silicate, xanthan gum and cellulose compounds. Thethickening agents employed include kaolin, pectin, xanthan gum andcellulose compounds. One preferred antihistamines decongestantcombination is pyrilamine and phenylephrine. Another preferredantihistamines decongestant combination is carbetapentane andchlorpheniramine.

[0058] Tannate suspension products are the therapeutic preparationscontaining active ingredients as tannate salt complexes. The therapeuticpreparations containing antihistamines, antitussives, anticholinergicsand decongestants are indicated for relief of nasal congestion such assinusitis, rhinitis and hay fever.

[0059] Typical combinations contain 30 mg of Carbetapentane tannate, 4mg of Chlorpheniramine tannate and 5 mg of Phenylephrine tannate, asactive ingredients; another contains 30 mg of Pyrilamine tannate and 5mg of Phenylephrine tannate; another contains 12.5 mg of Pyrilaminetannate, 5 mg of Phenylephrine tannate and 2 mg of Chlorpheniraminetannate as active ingredients; another contains 75 mg of Pseudoephedrinetannate and 25 mg of Diphenhydramine tannate.

[0060] The excipients commonly used in the formulations are as follows:sucrose, saccharin sodium and artificial flavor as flavoring agents,kaolin, pectin, xanthan gum, magnesium aluminum silicate (referred to asMAS), as thickening and anti-caking agents, glycerin as a co-solvent,sodium citrate, sodium phosphate monobasic and dibasic, citric acid,sodium benzoate and benzoic acid as a pH adjusting and buffering agents,methylparaben as a preservative, FD&C Red No. 40 and FD&C Blue No. 1 ascoloring agents and purified water.

[0061] Among the actives used, carbetapentane was obtained as thecitrate; phenylephrine, pseudoephedrine and diphenhydramine wereobtained as the hydrochloride; the pyrilamine and chlorpheniramine wereobtained as maleate salts.

[0062] The salts of the active ingredients are preferably dissolved inpurified water. However, other pharmaceutically acceptable liquids canbe substituted for water such as isopropyl alcohol, ethanol, glycerin,propylene glycol, mineral oil or mixtures thereof. This leads to thedissociation of the salt into its free base and conjugate acid forms.Another solution containing excess tannic acid in purified water isprepared. While stirring at low speeds, the solution of the salt isadded in small portions to the tannic acid solution. Because of thepresence of excess tannic acid, the free base form reacts with thetannic acid to form the tannate salt complex. Since the tannate saltcomplex formed is larger in size and has low solubility in purifiedwater, it is usually precipitated out of the solution.

[0063] The development of the process for the conversion of activeingredients to the tannate salt complexes is described below. The saltor free base of the active ingredients is dissolved in purified water orother pharmaceutically acceptable liquid. Purified water is taken in a600 ml beaker and stirred. While stirring, MAS is added in smallportions to obtain a dispersion. Once the MAS is dispersed, tannic acidis added to the mixture and stirred to form a uniform dispersion. Threedifferent batches of the MAS/tannic acid dispersion in purified waterare prepared for each active. In the three batches, the amount of tannicacid used is varied from an amount equal to that of the free base, twotimes that of the free base and three times that of the free base,present in the initial salt solution. The active ingredient solution isthen added in small portions, under light stirring, to the MAS/tannicacid dispersion. After all of the solution is added, the volume is madeup to 250 ml with purified water and stirring is continued for a periodof ten minutes. The MAS is used in this step to serve as an adherent ora solid support for the tannic acid molecules to facilitate theconversion process. In addition, it also prevents the clumping of thetannate salt formed, which aides in the isolation of the precipitate ofthe tannate salt complex formed from the solution. The dispersioncontaining the tannate salt complex is transferred to the suspendingmedium.

[0064] The salt solutions of carbetapentane, chlorpheniramine,pseudoephedrine, pyrilamine and diphenhydramine after addition to theMAS/tannic acid dispersion result in formation of copious amounts ofprecipitate at all three concentrations of tannic acid. However, in thecase of phenylephrine, the tannate salt complex shows partial solubilityin purified water.

[0065] The above batches are assayed for the formation of the tannatesalt complex. For all the actives, it is found that maximum conversion(greater than 97%) is achieved when tannic acid is used at three timesthe amount of the free base and so is chosen as the amount to be used inthe final formulation.

[0066] The conversions of the actives prepared are then transferred tosuspension vehicles without isolation or purification. Typicalsuspension vehicles are prepared comprising excipients such askaolin/pectin or xanthan gum as thickening agents. In addition, thesuspending vehicles also consist of sweetening, flavoring, coloring,pH-adjusting and buffering agents, preservatives and co-solvents. Theconversions of the actives are found to be viscous (3000-5000 cps). Theyare transferred to the suspending medium by pouring. The precipitateformed during the conversion is found to adhere slightly to the walls ofthe container and is scraped into the suspending medium using a spatula.Purified water is used to wash the remainder of the material into thesuspending medium. The conversions show significantly less adhesion tostainless steel containers than glass containers.

[0067] The Examples performed are as mentioned below. In all theExamples, the active ingredient is converted in-situ into the tannatesalt complex and then added to the suspension. The conversion processyields insoluble and soluble tannate salt complexes of the activeingredients. The tannate salt complexes obtained from the conversionstep are transferred without purification or isolation in suitablesuspending vehicles of kaolin/pectin or xanthan gum as thickeningagents.

EXAMPLE 1

[0068] Formation of the insoluble tannate salt complex by the conversionprocess:

[0069] The active solution of carbetapentane citrate is prepared bydissolving 24.4 g of carbetapentane citrate into 60 mL of water. 530 mlof purified water is placed in a mixing tank and 53.7 g of MAS is addedin small portions while mixing the water to form a dispersion. Once thedispersion is uniform and lump-free, 46.7 g of tannic acid (TA), (threetimes that of the free base of the active), is folded into thedispersion using a planetary mixer with a sweep blade. The sweepingaction to disperse the tannic acid is found to significantly simplifythe process by keeping the tannic acid particles from clumping andproviding greater uniformity of the dispersion. The salt solution isthen added in small portions, while continuing to stir the MAS/tannicacid dispersion using the planetary mixer. After all of the saltsolution is added, the weight is made up to 800 g with purified water.Mixing is continued and 5 g samples of the conversion after ten, twentyand thirty minutes of mixing are taken in a centrifuge tube. The samplesare subsequently centrifuged at 6500 rpm and the resulting supernatantsolution is assayed for the presence of active. At the end of thirtyminutes, a 10 g sample of the conversion is taken for assay of theactives. Similarly, the conversions of the other active ingredients areperformed in like manner and the weights of the materials are as shownin the table below.

[0070] 1. Carbetapentane: Amt. of Amt. of water (g) water (g) Total Amt.of (Salt Amt. of Amt. of (MAS/TA conversion Drug (g) solution) MAS (g)TA (g) Disp.) (g) 24.4 60.0 53.7 46.7 530.0 800.0

[0071]2. Chlorpheniramine: Amt. of Amt. of water (g) water (g) TotalAmt. of (Salt Amt. of Amt. of (MAS/TA conversion Drug (g) solution) MAS(g) TA (g) Disp.) (g) 15.51 60.0 43.44 32.76 600.00 800.00

[0072]3. Pyrilamine Amt. of Amt. of water (g) water (g) Total Amt. of(Salt Amt. of Amt. of (MAS/TA conversion Drug (g) solution) MAS (g) TA(g) Disp.) (g) 24.83 60.00 61.50 55.00 550.00 800.00

[0073] The results obtained from the above samples are as shown below:Assay (final Salt Soln Assay (% Dissolved) sample) Active (mg/g) 10 mins20 mins 30 mins (mg/g) Carbetapentane 299.1 0.08 0.08 0.09 30.3 (30.5)*Chlorpheniramine 216.6 0.12 0.13 0.14 19.9 (19.4)* Pyrilamine 290.9 0.100.10 0.11 29.2 (31.0)*

[0074] The formation of the insoluble tannate salt complex of theactive, as explained earlier, leads to the precipitation of the tannatesalt from solution as evidenced from the results above forcarbetapentane, pyrilamine, and chlorpheniramine. For all three actives,the amount of active ingredient present in solution at the ten, twentyand thirty minute mixing times is <0.2%.

EXAMPLE 2

[0075] Formation of the partially soluble tannate salt complex by theconversion process:

[0076] To illustrate the solubility of the tannate salt complex, and toobtain accurate values for the percent active dissolved, two experimentsare performed. In the first experiment, a salt solution of phenylephrineHCI is added to a MAS/tannic acid dispersion and the amount of activeingredient present in solution at the ten, twenty and thirty minutemixing times, is more than 47.0%.

[0077] Expt.-1 Phenylephrine HCI: Amt. of Amt. of water (g) water (g)Total Amt. of (Salt Amt. of Amt. of (MAS/TA conversion Drug (g)solution) MAS (g) TA (g) Disp.) (g) 12.5 40.0 43.8 30.9 600.0 800.0

[0078] Expt-I (RESULTS) Assay (final Salt Soln Assay (% Dissolved)sample) Active (mg/g) 10 mins 20 mins 30 mins (mg/g) Phenylephrine 276.537.14 47.6 47.6 16.8 (18.1)*

[0079] In a second experiment commercial phenylephrine tannate rawmaterial is added to a dispersion of MAS and mixed for a period of tenminutes. The results obtained are as below:

[0080] Expt-II-Phenylephrine Tannate: Amt. of Amt. of water (g) water(g) Total Amt. of (Salt Amt. of Amt. of (MAS/TA conversion Drug (g)solution) MAS (g) TA (g) Disp.) (g) 1.56 n/a 5.48 n/a 85.00 100.0

[0081] Expt-II (RESULTS) 10 minute 10 minute Assay mixing sample mixingsample (final sample) Active Amt. (mg/g) % Dissolved (mg/g)Phenylephrine 9.5 25.1 37.8 (40.6)*

[0082] Phenylephrine HCI is freely soluble (about 100.0% soluble) inwater. From the results for Expt-I, it can be seen that the tannate saltcomplex is 57% soluble in water. This is further illustrated by theresults from Expt-II which show that at least 25.0% of the commerciallyavailable tannate salt complex is soluble.

EXAMPLE 3

[0083] Formation of the insoluble tannate salt complex by the conversionprocess using organic solvents.

[0084] The active solution of Dextromethorphan hydrobromide is preparedby dissolving 1.180 g of drug into 85:15 mixture of purified water andethanol. 400 mL of purified water was taken in a 1 L mixing tank and2.685 g of MAS is added in small portions while mixing the water forforming a dispersion. Once the dispersion is uniform and lump-free,2.722 g of tannic acid (TA) (three times that of the free base of theactive) is folded into the dispersion using a planetary mixer with asweep blade. The sweeping action to disperse the tannic is found tosignificantly simplify the process by keeping the tannic acid particlesfrom clumping and providing greater uniformity of the dispersion. Thesalt solution is then added in small portions, while continuing to stirthe MAS/tannic acid dispersion using the planetary mixer. After all ofthe salt solution is added, the weight is made up to 500 g with purifiedwater.

[0085] 1. Dextromethorphan: Amt. of Amt. of water/ethanol water (g)Total Amt. of (g) Amt. of Amt. of (MAS/TA conversion Drug (g) (Saltsolution) MAS (g) TA (g) Disp.) (g) 1.180 51.180 2.685 2.726 405.411 500

EXAMPLE 4

[0086] Formation of the tannate salt complex using the free base of theactive ingredient in the conversion process:

[0087] The active solution of brompheniramine is prepared by dissolving23.538 g of drug into 100 mL of purified water. 500 mL of purified wateris taken in a 1 L mixing tank and 2.5 g of MAS is added in smallportions while mixing the water to form a dispersion. Once thedispersion is uniform and lump-free, 70.614 g of tannic acid (TA),(three times that of the free base of the active), is folded in to thedispersion using a planetary mixer with a sweep blade. The sweepingaction to disperse the tannic acid is found to significantly simplifythe process by keeping the tannic acid particles from clumping andproviding greater uniformity of the dispersion. The salt solution isthen added in small portions, while continuing to stir the MAS/tannicacid dispersion using the planetary mixer. After all of the saltsolution is added, the weight is made up to 800 g with purified water.

[0088] 1. Brompheniramine: Amt. of Amt. of water (g) water (g) TotalAmt. of (Salt Amt. of Amt. of (MAS/TA conversion Drug (g) solution) MAS(g) TA (g) Disp.) (g) 23.538 100 25.000 70.614 595.614 800

EXAMPLE 5

[0089] Preparation of a suspension with kaolin/pectin as thickeningagents: % w/v mg/5 mL Pyrilamine Tannate 0.250% 12.500 PhenylephrineTannate 0.100% 5.000 Chlorpheniramine Tannate 0.040% 2.000 SaccharinSodium 0.05% 0.003 Sucrose 10.00% 0.500 Glycerin 7.500% 0.375 Magnesiumaluminum Silicate 1.750% 0.088 Kaolin 1.600% 0.080 Pectin 1.750% 0.088Methylparaben 0.200% 0.010 Benzoic Acid 0.100% 0.005 FD&C Red No. 400.020% 0.001 Strawberry Flavor 0.050% 0.003 Purified Water qs to volumeN/A

[0090] The saccharin sodium, sucrose, kaolin and a part of the MAS aredispersed in purified water in stainless steel mixing tank, using asuitable stirrer. The coloring agent and the artificial strawberryflavor are then added and mixing is continued to generate the suspendingmedium.

[0091] The pyrilamine maleate is dissolved in purified water. In anothermixing tank MAS and tannic acid are dispersed in purified water using amixer. Once a uniform dispersion is achieved, the solution of the drugis poured in small portions to the tank while stirring. After all of thesolution is transferred, stirring is continued for ten minutes. Thecontents of the tank are then transferred to the suspending medium.

[0092] The phenylephrine HCI is dissolved in purified water. In anothermixing tank, MAS and tannic acid are dispersed in purified water using amixer. Once a uniform dispersion is achieved, the solution of the drugis poured in small portions to the tank while stirring. After all of thesolution is transferred, stirring is continued for ten minutes. Thecontents of the tank are then transferred to the suspending medium.

[0093] The pectin is dispersed in glycerin in a mixing tank using amixer. The benzoic acid and methylparaben are then dispersed in theglycerin mixture in the tank. The glycerin mixture is added to thesuspending medium containing the active ingredients and mixed to get auniform dispersion.

[0094] Finally, purified water is added to make up to the suspension tothe required volume and mixed to obtain an elegant product.

EXAMPLE 6

[0095] Preparation of a suspension with xanthan gum as thickening agent:% w/v mg/5 mL Pseudoephedrine Tannate 1.500% 75.000 DiphenhydramineTannate 0.500% 25.000 Saccharin Sodium 0.300% 0.015 Sucrose 10.000%0.500 Glycerin 7.500% 0.375 Magnesium Aluminum Silicate 0.800% 0.040Xanthan gum 0.520% 0.026 Dibasic sodium phosphate 1.000% 1.050Methylparaben 0.200% 0.010 Sodium benzoate 0.100% 0.005 FD&C Red No. 400.040% 0.002 Strawberry Flavor 0.500% 0.025 Purified Water qs to volumeN/A

[0096] The sodium phosphate dibasic is dissolved in purified water in asuitable stainless steel mixing tank. The MAS, followed by xanthan gum,is dispersed in the solution. The coloring agent FD&C Red No. 40 and theartificial strawberry flavor are then added and mixed to generate thesuspending medium. In a separate mixing tank, the MAS and tannic acidare dispersed in water using a suitable stirrer. Mixing is continueduntil a uniform dispersion is achieved.

[0097] Pseudoephedrine HCI is dissolved in purified water. Whilestirring the MAS/tannic acid dispersion in the mixing tank at low speed,the pseudoephedrine HCI solution is transferred in small portions to thedispersion. Stirring is continued for a minimum of ten minutes. Aftermixing, the contents of the tank are transferred to the suspendingmedium and mixed for a period of five minutes. Similarly, thechlorpheniramine maleate is converted to the tannate salt andtransferred to the suspending medium.

[0098] The sodium benzoate and methylparaben are dispersed in glycerinin a mixing tank using a suitable mixer. The glycerin mixture is thenadded to the suspending medium and mixed to achieve a uniformdispersion. Finally, purified water is added to make up the suspensionto the required volume.

EXAMPLE 7

[0099] Preparation of a suspension using HPMC and propylene glycol inthe conversion step: % w/y mg/5 mL Pyrilamine Tannate 0.250% 12.500Phenylephrine Tannate 0.100% 5.000 Chlorpheniramine Tannate 0.040% 2.000Saccharin Sodium 0.05% 2.500 Sucrose 10.00% 500.000 Glycerin 7.500%375.000 Propylene Glycol 2.000% 100.000 HPMC 1.750% 87.500 Kaolin 1.600%80.000 Pectin 1.750% 87.500 Methylparaben 0.200% 10.000 Benzoic Acid0.100% 5.000 FD&C Red #40 0.020% 1.000 Strawberry Flavor 0.050% 3.000Purified Water qs to volume n/a

[0100] The saccharin sodium, sucrose, kaolin and a part of the HPMC aredispersed in purified water in stainless steel mixing tank, using asuitable stirrer. The coloring agent and the artificial strawberryflavor are then added and mixing is continued to generate the suspendingmedium.

[0101] The pyrilamine maleate is dissolved in purified water. In anothermixing tank HPMC and tannic acid are dispersed in 75:25 purifiedwater/propylene glycol mixture using a mixer. Once a uniform dispersionis achieved, the solution of the drug is poured in small portions to thetank while stirring. After all of the solution is transferred, stirringis continued for ten minutes. The contents of the tank are thentransferred to the suspending medium. The phenylephrine HCl is dissolvedin purified water. In another mixing tank, HPMC and tannic acid aredispersed in 75:25 purified water/propylene glycol mixture using amixer. Once a uniform dispersion is achieved, the solution of the drugis poured in small portions to the tank while stirring. After all of thesolution was transferred, stirring is continued for ten minutes. Thecontents of the tank are then transferred to the suspending medium. Thepectin is dispersed in glycerin in a mixing tank using a mixer. Thebenzoic acid and methylparaben are then dispersed in the glycerinmixture in the tank. The glycerin mixture is added to the suspendingmedium containing the active ingredients and mixed to provide a uniformdispersion.

[0102] Finally, purified water is added to make up to the suspension tothe required volume and mixed to obtain an elegant product.

[0103] The foregoing is considered as illustrative only of theprinciples of the invention. Further, various equivalents to theingredients may be substituted without departing from the scope thereofand it is desired, therefore, that only such limitations shall be placedthereon as are imposed by the prior art and which are set forth in theappended claims.

What is claimed is:
 1. A manufacturing process for the in-situconversion and incorporation of a salt or free base of an activepharmaceutical ingredient selected from the group consisting of anantihistamine, a decongestant, an antitussive and an anticholinergic forincorporation into a therapeutic liquid or semi-solid dosage form, theprocess comprising the steps of: (a) dissolving the salt or free base ofthe active pharmaceutical ingredient in a pharmaceutically acceptableliquid to form a solution at a maximum temperature and pH value, thatdoes not cause decomposition of the active pharmaceutical ingredient;(b) separately adding a dispersing agent and tannic acid to apharmaceutically acceptable liquid, under stirring, to form adispersion; (c) transferring the solution from step (a), in portions tothe dispersion in step (b) under stirring, to form a precipitate of atannate salt complex of the active pharmaceutical ingredient; and (d)combining the tannate salt complex of the active pharmaceuticalingredient without isolation or purification with pharmaceuticallyacceptable excipients to generate a therapeutic dosage form.
 2. Theprocess according to claim 1 wherein the antihistamine activepharmaceutical ingredient is selected from the group consisting of:Carbinoxamine, Chlorpheniramine, Pyrilamine, Pheniramine, Phenindamine,Diphenhydramine, Bromodiphenhydramine, Brompheniramine, Loratadine,Desloratadine, Fexofenadine, Cetirizine, Hydroxyzine, Promethazine,Acrivastine, Triprolidine, Meclizine, Dimenhydrinate, Triplennamine,Doxylamine, Diphenylpyrilamine, Trimeprazine; and Chlorcylizine.
 3. Theprocess according to claim 1 wherein the antitussive activepharmaceutical ingredient is selected from the group consisting of:Carbetapentane, Dextromethorphan, Diphenhydramine, Codeine, Hydrocodone,Oxycodone, and Morphine.
 4. The process according to claim 1 wherein thedecongestant active pharmaceutical ingredient is selected from the groupconsisting of: Phenylephrine, Pseudoephedrine, Ephedrine,Diphenhydramine, Cyproheptadine, Phenyltoloxamine, and Clemastine. 5.The process according to claim 1 wherein the anticholinergic activepharmaceutical ingredient is methscopolamine.
 6. The process accordingto claim 1 wherein the antihistamine and decongestants activeingredients are provided as the bitartrate, maleate, citrate, chloride,bromide, acetate or sulfate salt.
 7. The process according to claim 1wherein the tannic acid provided in step (b) is natural or synthetic. 8.The process according to claim 1 wherein the dispersing agent providedin step (b) is selected from the group consisting of magnesium aluminumsilicate, xanthan gum and cellulose compounds.
 9. The process accordingto claim 1 wherein the pharmaceutically acceptable liquid in steps (a)and (b) is selected from the groups consisting of purified water,isopropyl alcohol, ethanol, glycerin, propylene glycol, mineral oil andmixtures thereof.
 10. The process according to claim 9 wherein thepharmaceutically acceptable liquid in steps (a) and (b) is purifiedwater.
 11. The process according to claim 1 wherein without isolation orpurification of the tannate salt or complex of the active pharmaceuticalingredient, the additional steps are: (d) separately adding athickening, suspending, coloring, sweetening and flavoring agent towater under stirring, to form a dispersion; (e) adding the precipitatefrom step (c) to the dispersion in step (d), under stirring to form amixture containing the tannate salt complex of the active pharmaceuticalingredient; (f) separately adding a preservative, pH adjusting andanti-caking agents to pharmaceutically acceptable liquid under stirringto form a dispersion; and (g) adding the dispersion from step (f) to themixture from step (e) under stirring, to generate a suspension dosageform, at a pH range of 3.5-8.0.
 12. The process according to claim 1wherein a mixture of antihistamine tannate and decongestant tannatesalts are formed in step (c).
 13. The process according to claim 12wherein the antihistamine tannate and decongestant tannate salts in step(c) comprise carbetapentane tannate, phenylephrine tannate andpyrilamine tannate.
 14. The process according to claim 12 wherein theantihistamine tannate and decongestant tannate salts in step (c)comprise pyrilamine tannate and phenylephrine tannate.
 15. The processaccording to claim 12 wherein the antihistamine tannate and decongestanttannate salts in step (c) comprise pseudoephedrine tannate andchlorpheniramine tannate.